The present report describes toxicological approaches to evaluate inflam- matory potency of heavy metal compounds deposited in the lung. Although inhalation exposure is a well-accepted method to study effects of pulmonary toxicants, it requires expensive facilities and many man-hours to complete experiments. Intratracheal (i.t.) instillation, an alternative and simple method to expose animals to toxicants via airways, has been proved to be useful to investigate the pulmonary clearance of heavy metals. However, acute inhalation exposure caused more severe inflammatory lung injury than i. t. instillation when the same amount of nickel sulfate was administered in the rat. Among several biochemical inflammatory indices such as some enzyme activities and the protein concentration in bronchoalveolar lavage (BAL) fluid, only lactate dehydrogenase (LDH) activity increased linearly with a wide range of doses of heavy metals. The increase in polymorphonuclear leukocytes (PMN) in BAL fluid, a cytological index of inflammatory responses of the lung, is believed to reflect pulmonary toxicity of heavy metals. However, more extensive study is required to elucidate the mechanism of transpulmonary PMN infiltration upon heavy metal insult. In addition to the linearity between LDH activity in BAL fluid and doses of heavy metals, the increase in this cytosolic enzyme activity is associated with cell lysis in the bronchoalveolar milieu and appears to be the best index to evaluate pulmonary inflammatory potency of heavy metals.

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Japan was defeated in World War II and almost all of the nation was demoralized by the destruction and damage to much of the nation. The medical and health care system during and before World War II needed to be reformed radically and fundamentally since almost all medical and health institutes were destroyed. On the other hand, many health personnel came back from overseas after the war. Japanese modern medicine had developed on the basis of German medicine; however, many aspects of American medicine, including public health and democracy, were rapidly introduced following the end of World War II. The American type of health center was established and many laws concerning medical and health care were enacted in 1947-1948. One of them was "The Health Center Law."
The National Health Insurance Act was enacted in 1958 and the total population has been covered by health insurance plans since 1961. Many physicians quit the health centers and they have worked as clinicians under the National Health Insurance scheme, because health centers were introduced before adequate education and research existed in the field of public health. On the other hand, the health insurance scheme was in its golden age during the high economic growth period of the 1960s. Japan has succeeded in all forms of modern technology and economy for the past 30 years and is now one of the top nations in the field of medical and health care, such as the numbers of clinics and hospitals and beds, the frequency of consulting with a doctor, length of hospital stay, examinee rates in mass health examinations in the community and workplace and so on.
Health conditions have changed drastically from the 1950s to the present. Therefore, health centers do not fit current health needs. For example, mortality from tuberculosis, acute infections diseases and also stomach and uterus cancers and apoplexy have decreased rapidly while mortality from chronic diseases, especially lung, breast and rectal cancers, and myocardial infarction have increased gradually. Changes of life style resulting from rapid economic growth are suspected to be important causes of the change in the prevalence of these diseases.
Mass health examination was important and effective as a preventive measure against tuberculosis, especially as a means of early detection and early treatment. However, it is not now effective against chronic diseases. The screening examination has resulted in identifying many patients suspected of being ill. Every examiner must be able to distinguish pathologic findings from physiologic changes of aging. Every patient must, therefore, understand his/her individuality and evaluate the result of his/her efforts to improve life style by receiving a health examination. Accordingly, the aim of health examination has changed from early detection to health support for the examinee.
During the decades when life expectancy was less than 50 years of age, it was not necessary for people to plan for retirement. Moreover, there was little burden on younger genarations to provide care for the aged people because there were few old people more than 70 years of age and the birth rate was high. Nowadays, elderly people face many years of life after retirement and there are too many aged people in relation to the number of younger persons.
As for medical care services, many new medical needs have emerged in resent years, including "quality of life, " "palliative medicine in terminal care, " "establishment of a primary care system" and "comprehensive care connecting health and medical care with welfare" etc.
Improved living standards resulting from economic growth, called the "economic miracle" internationally, have helped to bring about a rapid and wide range of change in daily lifestyle, such as eating habits, working conditions and environment.

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Molecular cancer epidemiology is a relatively new strategy for malig nancies. This strategy has made it possible to diagnose the predisposition to cancer. An individual is said to have a predisposition to cancer when a tumor-suppressor gene is inactivated in germ-line cells. Mainly the inactivation of the tumor-suppressor gene is caused by mutations at the coding region of the gene. However, we clarified that point mutations or hypermethylations of the retinoblastoma tumor-suppressor gene (RB) also cause inactivation of the gene, resulting in retinoblastoma. On the other hand, studies to improve the diagnosed predisposition to cancer have not been performed. We therefore started a basic study for this purpose. As the first example of limiting the predisposition to cancer, the cases with a point mutation at the RB promoter region might be good candidates. In these carriers, only the RB promoter region is inactivated in spite of a lack of abnormalities in the coding region. Therefore, if the RB promoter activity is recovered by drugs, predisposition to retinoblastoma should be limited. As the second example, Li-Fraumeni syndrome in which the p53 gene is hereditarily mutated might be a good candidate. Recently p53 has been reported to stimulate the WAF1 gene, and the WAF1 protein to inhibit cdk activity, which inactivates the RB gene product by phosphorylation. In addition, we found that p53 up-regulates the promoter activity of the RB gene. These findings suggest that p53 directly or indirectly activates RB at the transcriptional or post-transcriptional level. Therefore, reactivation of the WAF1 or RB gene by certain drugs might compensate for the loss of function of p53 in Li-Fraumeni syndrome. We then suggest that it might be possible to prevent cancer by enhancing some intact target genes of the genetically inactivated tumor-suppressor gene. We term this new strategy "generegulating chemoprevention." To test this hypothesis it is important to clarify the structure of the RB promoter. In summary we found that RBF-1 and ATF sites are the core promoter regions, that the neighboring E2F site is a silencer site, and that E4TF1 preferentially binds to the RBF-1 site. We then speculate that drugs interfering with the binding of the E2F complex might become good candidates enhancing RB promoter activity. To find drugs regulating the promoters of these genes, it is reasonable to try G1 arresting drugs, because WAF1 and RB are thought to arrest cells at the G1 phase. Actually we found seveval drugs causing G1 arrest. They are several flavonoids which we ingest daily from vegetables and fruits, or prostaglandin D₂ and its metabolite. In summary, we propose that "generegulating chemoprevention" will be a useful method for molecular cancer epidemiology.

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To investigate the effects of long-term physical exercise on humans, body composition, cardiovascular function and serum lipids were measuted for a training period of 20 months in 8 men and 8 women, aged 36-67 years who were mildly obese. The subjects participated in physical training for 90 minutes about twice a week for 20 months. The intensity of training was at most 60% VO_2max for each subject as calculated by karvonen's formula.
The results are summarized as follows:
(1) Body weight and estimated body fat weight decreased from baseline after the training in both sexes. The percentage decreases in body weight and estimated body fat weight in men were about threeefold those in women.
(2) Following the training, heart rate, blood pressure and rate pressure product (RPP) at rest had significantly decreased from initial levels in both sexes.
(3) Following the training, the physical work capacity at a heart rate of 150bpm significantly increased, and systolic blood pressure at the heart rate of 150bpm significantly decreased from baseline levels in both sexes.
(4) Following the training, the serum HDL-cholesterol and HDL-/total-cholesterol ratio significantly increased from baseline, and serum triglycerides and total cholesterol also significantly decreased from baseline levels in both sexes.
These results suggest that long-term physical training with moderate intensity improves body composition, cardiovascular function and serum lipids in mildly obese middle-aged men and women, and reduces the risks for coronary heart disease.

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The relationships among seven lifestyle factors including stress, which is focused on as a risk factor for cardiovascular disease recently, social network, blood pressure and serum lipids in the elderly were examined in a cross sectional study of 85 males and 65 females aged 60 years or over in the city of Sayama, Saitama Prefecture. The seven lifestyle factors were as follows: (1) amount of alcohol consumption, (2) cigarette smoking, (3) Physical exercise, (4) sleeping time per night, (5) nutritional balance, (6) body weight, and (7) stress. As social network factors, marital status and coping factor for stress and/or anxiety were introdued. Stressful life events strongly associated with stress status were also discussed.
In this study, it was clear that age, alcohol consumption, stress status and stressful life events caused higher blood pressure. On the other hand, the social network was associated with lifestyle status and a controlled blood pressure level. Obesity and physical exercise were significantly associated with serum lipids. There results suggest that it is very important for the maintenance and promotion of health and risk reduction of disease among the elderly to control socio-psychological factors such as stress and stressful life event, and that a social network helps maintain a healthy lifestyle.

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I investigated 4960 accidental injuries which occurred among elementary school children between April 1991 and March 1992, using reports of school accidents submitted to the Shiga branch of the National Studium and School Health Center of Japan. Data on six school environmental factors (i.e. the areas of school land, schoolhouse, gymnasium and all classrooms, the number of children per class, and the total number of children in each school) for 223 elementary schools were gathered. From these data, the relationship between the incidence rates of injuries and the above school environmental factors were analyzed.
The overall average incidence rate for all injuries combined was 5.43 cases per 100 children. For all injuries and fractures which occurred at smaller schools, the incidence rates tended to increase with the areas of school land, schoolhouse, gymnasium and all classrooms, and to decrease as the number of children per class and the number of children in the school increased. These results may have been biased by the fact that only injuries treated at a cost of at least 3000 yen were reported.
In the process of stepwise multiple regression analysis between the injury-rates and environmental factors, a few variables relating to types of injuries were included as statistically significant factors in the well-fitted equations, but the coefficients of determination (squared multiple correlation coefficients) in the equations were small.

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We studied changes of the complement pathway activities and the content of C3 in sera of mice, administered BeCl₂ (containing 5μg of Be per mouse) or CuCl₂ (containing 5μg of Cu per mouse) by a single subcutaneous injection.
The value of the classical complement pathway activity (CH50) of the Be group 3 days after administration was significantly higher than that of the control group (P<0.001). It was significantly lower than in the control group after 7 days (P<0.001). On the other hand, the CH50 value of the Cu group 3hr after administration tended to increase, however, it was significantly lower than in the control group after 7 days (P<0.01). The change of the alternative complement pathway activity (ACH50) value of the Be group was similar to the change of the CH50 value of the group. The ACH50 value of the Cu group 3 days after administration tended to increase but it was the same as the ACH50 value of the control group after 7 days. The C3 contents of both the Be and Cu groups 3 days after administration were significantly higher than in the control group (P<0.001).
The aspartate aminotransferase (AST) activity of the Be group 7 days after administration was significantly higher than that of the control group (P<0.01). By contrast, AST activity of the Cu group 3hr after administration was significantly higher than in the control group (P<0.05). The value of the alanine aminotransferase (ALT) activity of the Be group was low (P<0.01), but that of the Cu group was high (P<0.05), 3hr after administration. These values of both groups after 7 days, however, were significantly higher than in the control group (P<0.05). The AST/ALT ratio in mice was very high at 3hr, and it remained high by 7 days after Be injection. On the other hand, the ratio of the Cu group was almost constant for 7 days after Cu injection.
Thus, these values changed with relative expedition after Be injection. Therefore, we confirmed that measurements of complement activities and the content of C3 were valuable indices for assaying acute effects of Be on mice.

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To establish reference values for bone mineral density (BMD), a population survey was carried out in a fishing community in Wakayama Prefecture. The BMD measurements of the lumbar spine (L2-L4) and proximal femur (femoral neck, trochanter and Ward's triangle area) were performed by sex and age, using dual-energy X-ray absorptiometry. Four hundred subjects, aged 40 to 79 years, were recruited randomly to give 50 persons in each of eight age-sex strata from a list of 2, 261 residents (1, 028 men and 1, 233 women) living in a fishing village.
The validity of sampling methods was assessed using a questionnaire about lifestyle factors, which was used for all residents aged from 40 to 79 years in the baseline survey.
There were no significant differences between the subjects for BMD measurements and all the residents of the community in the frequencies of past history of diseases, healthy habits, food intakes, and rates of smoking, alcohol drinking, coffee and green tea consumption. These findings suggested that the present study population could be considered representative of samles obtained from the entire population in the fishing community.
The results of BMD measurements in these subjects, who were selected at random, showed that except for a slightly high BMD of the lumbar spine in men in their 60's, the mean BMD of the lumbar spine and the three proximal segments of the femur decreased with increasing age in both sexes.

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We investigated the in vitro effects of ultraviolet A (UVA) irradiation on human neutrophil function. For measurements of reactive oxygen species (ROS) and serum opsonic activity, chemiluminescence was used. Chemotactic activity was determined by the Boyden technique.
In this study, for detection of the effects of UVA irradiation on human neutrophil ROS production, we used luminol-dependent and lucigenin-dependent chemiluminescence, in addition to two kinds of action stimuli, opsonized zymosan and phorbol myristate acetate (PMA).
We found that UVA irradiation at low doses of UVA (0.2-0.4J/cmcm²) did not affect the generation of OCl^-, and it was suggested that high doses of UVA (0.6-1.0J/cmcm²) suppressed OCl^- production by inactivating the signalling cascade which induces ROS on the membrane surface of neutrophils. No significant difference was observed in the chemotactic activity. The serum opsonic activity was increased by UVA irradiation. These results suggest that low doses of UVA do not impair neutrophil phagocytic activity, and that higher doses of UVA suppress the ROS generating capacity of neutrophils. However, to compensate for ths suppression, serum opsonic activity was induced, so it seemed that the neutrophil-related immune system could be retained.

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